Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition

Abstract

Cancer-Associated Fibroblasts (CAFs) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression, through pro-tumour cross-talk and the generation of fibrosis (physical barrier to drugs). CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumour stroma and its prognostic significance. Herein we show that high expression of SLC7A11 in PDAC tumour stroma (but not tumour cells) is independently prognostic of poorer overall survival. We demonstrate using orthogonal approaches that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis, and that SLC7A11 inhibition significantly decreases their proliferation, reduces their resistance to oxidative stress and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, our paradigm-shifting work demonstrates the need to inhibit SLC7A11 in the PDAC stroma, as genetic ablation of SLC7A11 in PDAC cells alone is not enough to reduce tumour growth. Finally, our work validates that a nano-based gene-silencing drug against SLC7A11, developed by our group, reduces PDAC tumour growth, CAF activation and fibrosis in a mouse model of PDAC.

Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer?

“…The presence of the microenvironment and stroma in the tumour explant model represents a powerful tool to study the effects of gene-therapeutic nanoparticles on both tumour and stroma [ 94 ]. We recently demonstrated the utility of the tumour explant model to test the therapeutic effects of inhibiting SLC7A11 using either an siRNA-nanomedicine or a clinical-grade SLC7A11 inhibitor, sulfasalazine [ 95 ]. We demonstrated anti-tumour and stromal CAF reprogramming [ 95 ].…”

“…We recently demonstrated the utility of the tumour explant model to test the therapeutic effects of inhibiting SLC7A11 using either an siRNA-nanomedicine or a clinical-grade SLC7A11 inhibitor, sulfasalazine [ 95 ]. We demonstrated anti-tumour and stromal CAF reprogramming [ 95 ].…”

“…For such therapeutic strategies to be evaluated, preclinical models that contain matched patient tumour and stroma would be highly beneficial and potentially even necessary. We recently demonstrated the utility of the ex vivo tumour explant model to test therapeutic inhibition of an amino acid transporter SLC7A11 using an siRNA nanoparticle and a clinical-grade pharmacological inhibitor, sulfasalazine [ 95 ]. Importantly, upregulation of SLC7A11 in stromal cells of PDAC correlates with poor patient survival [ 95 ].…”

“…We recently demonstrated the utility of the ex vivo tumour explant model to test therapeutic inhibition of an amino acid transporter SLC7A11 using an siRNA nanoparticle and a clinical-grade pharmacological inhibitor, sulfasalazine [ 95 ]. Importantly, upregulation of SLC7A11 in stromal cells of PDAC correlates with poor patient survival [ 95 ]. Silencing of SLC7A11 expression using our siRNA nanoparticle in patient derived PDAC explants demonstrated potent anti-tumour and anti-stromal effects, and similar results were observed with sulfasalazine treatment of the patient explants [ 95 ].…”

“…Importantly, upregulation of SLC7A11 in stromal cells of PDAC correlates with poor patient survival [ 95 ]. Silencing of SLC7A11 expression using our siRNA nanoparticle in patient derived PDAC explants demonstrated potent anti-tumour and anti-stromal effects, and similar results were observed with sulfasalazine treatment of the patient explants [ 95 ]. This reinforces the ability of the ex vivo whole-tissue explant model to test such therapeutic strategies, and their potential to rapidly model tumour and stromal function can make them key components of novel clinical trial design to select patients that would benefit from such strategies.…”